Erythropoietin and Resistant Hypertension in CKD Suzanne M. Boyle, MD, and Jeffrey S. Berns, MD

Summary: There is a well-documented association between erythropoiesis-stimulating agents (ESAs) and hypertension in chronic kidney disease. Studies suggest that the mechanism for this is multifactorial. First, some chronic kidney disease patients may have a limited ability to accommodate a rapid increase in red cell volume because of a decreased glomerular filtration rate, left ventricular hypertrophy, and decreased arterial compliance. Second, there is likely a direct vasoconstrictor effect of ESAs. Although no large randomized controlled trials of ESAs have been designed with blood pressure as an a priori outcome, several metaanalyses have explored this relationship and generally support the existence of ESA-induced hypertension. There are as of yet no data directly linking ESA-induced hypertension with increased cardiovascular morbidity and mortality. Despite this, clinicians should be vigilant for ESA-induced hypertension, use caution when using ESAs in patients with resistant hypertension, and be attentive to the rate of hemoglobin increase in patients with poorly controlled blood pressure. Semin Nephrol 34:540-549 C 2014 Elsevier Inc. All rights reserved. Keywords: Erythropoietin-stimulating agents, anemia, hypertension, chronic kidney disease

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ince the early years of erythropoiesis-stimulating agent (ESA) use, there has been a welldocumented relationship between recombinant erythropoietin use and blood pressure (BP) increase.1,2 This relationship, although broadly recognized, is not well-elucidated at either a mechanistic or clinical level. In this review, we examine evidence supporting a potential mechanistic role for recombinant erythropoietin in BP increase. In addition, we consider the available literature from observational studies and randomized controlled trials (RCTs) to ascertain whether or not such a mechanistic association between ESA and hypertension might bear relevance at a clinical level.

EARLY CLINICAL OBSERVATIONS The first observations of the potential association between ESA use and hypertension emerged in the late 1980s. In the phase I and II trials of recombinant human erythropoietin, 4 of 25 hemodialysis (HD) patients developed de novo or exacerbated hypertension. One of these patients suffered a grand mal seizure, which was attributed to the increase in BP.3 A phase III trial by Eschbach et al4 evaluated trends in BP and antihypertensive medication use in 251 HD patients after 3 months Perelman School of Medicine at the University of Pennsylvania, Hospital of the University of Pennsylvania, Philadelphia, PA. Financial disclosure: none. Conflict of interest statement: Dr. Berns serves on the Executive Committee for an on-going Amgen-sponsored clinical trial with darbepoetin alpha. Address reprint requests to Jeffrey S. Berns, MD, Perelman School of Medicine at the University of Pennsylvania, Hospital of the University of Pennsylvania, 3400 Spruce St, Philadelphia, PA 19104. E-mail: [email protected] 0270-9295/ - see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.semnephrol.2014.08.008

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of ESA therapy. Of these, 88 patients (35%) developed an increase in diastolic BP of at least 10 mm Hg or required escalation of their antihypertensive regimen. Among patients who were not hypertensive at baseline (71 patients), 44% (31 patients) experienced an increase in diastolic BP of at least 10 mm Hg and 32% (23 patients) initiated antihypertensive therapy. Seizures were observed in 5.4% of the study participants (18 patients); 10 of these seizure events occurred during the first 3 months of therapy and paralleled the period of steepest increase in hematocrit level. It was observed that some of these seizures were accompanied by the onset of uncontrolled hypertension.4 In 1989, a small study of 10 HD patients in the United Kingdom reported the development of hypertensive encephalopathy in one patient whose BP increased to 220/140 mm Hg from a baseline of 170/90 mm Hg. This was associated with an increase in hemoglobin level of nearly 4 g/dL over approximately 6 weeks.5 ESA doses administered during these trials often were substantially higher than doses administered today and hemoglobin levels often increased much more rapidly than is considered safe in current practice. For example, one patient who developed hypertension and seizures in the phase I/II trial had a hematocrit increase from 16% to 37% within 5 weeks of therapy initiation. The dose administered to this patient was nearly 5 times the current recommended dose and corresponded with a rate of increase of hematocrit that is well beyond that established by current practice guidelines.6,7

SYSTEMIC HEMODYNAMIC EFFECTS OF ANEMIA AND ITS CORRECTION In the setting of anemia, several compensatory physiologic responses occur that tend to maximize oxygen delivery to tissues. Peripheral vascular resistance Seminars in Nephrology, Vol 34, No 5, September 2014, pp 540–549

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typically is lower in patients with anemia than in subjects with normal hematocrit levels, a response known as hypoxic vasodilation. Given the relatively low red cell volume in the anemic state, blood viscosity also is reduced, and thus cardiac output is increased in a compensatory fashion, creating a hyperdynamic state.8,9 Several investigations over the years have shown this physiology as well as its reversal when the anemic state is corrected. For instance, Neff et al10 conducted a study in both HD patients and patients with normal kidney function, in which cardiac output, total peripheral resistance (TPR), and blood and plasma volume were measured. A subcohort of the study also received blood transfusions. After the transfusion-induced increase in hematocrit, the cardiac index decreased and TPR increased, with an increase in both diastolic BP and mean arterial pressure (MAP). These results were found to be reversible when hematocrit levels were allowed to decrease in the HD patients in the weeks after the transfusion. Similar trends in these physiologic parameters were found in a cohort of HD patients receiving ESA agents in the absence of transfusion.11 In this study, both red blood cell mass and plasma volume increased. The authors suggested that impaired kidney function limits the ability to normally regulate plasma volume, making these patients susceptible to volume-dependent hypertension. Highlighting the potential differences in the physiology of the chronic kidney disease (CKD) population versus that of subjects with adequate renal function and normal hematocrit, Lundby et al12 performed a study of 8 healthy subjects who received ESA therapy for a total of approximately 14 weeks along with serial measurements of red cell volume, plasma volume, and total blood volume, as well as plasma renin activity and aldosterone. As average hemoglobin increased from 14.2 ⫾ 0.6 g/dL at baseline to 17.1 ⫾

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0.5 g/dL at the end of the study, red cell volume significantly increased in parallel with a reduction in plasma volume of similar magnitude. Thus, there was no significant net change in total blood volume. Both plasma renin activity and aldosterone significantly decreased during the study, and MAP values showed a trend toward higher values. Investigating the temporal response of BP to ESA administration, Hon et al13 conducted a double-blind, cross-over study on 9 HD patients in which BP was measured by an automatic cuff at 5-minute intervals for 60 minutes after administration of either saline or an ESA. The investigators found no significant difference in BP between the intervention strategies or between the baseline and 60-minute measurements. Despite the small sample size, this study suggested that there is not an immediate pressor effect of ESA therapy and that perhaps chronic exposure or the rate of hematocrit increase might be more influential factors. Collectively, these studies show the core elements of some of the proposed hypothetical frameworks for ESA-induced hypertension. Namely, de novo or exacerbated hypertension might be a product of an increase in TPR owing to increased red cell mass and hence reversal of hypoxic vasodilation, along with failure to appropriately reverse the hyperdynamic state of chronic anemia with maintenance of high cardiac output despite increased hematocrit (Fig. 1). Given that patients with CKD may have a limited ability to undergo the physiologic changes necessary to accommodate rapid changes in red cell volume because of their reduced GFR as well left ventricular hypertrophy and decreased arterial compliance, it is plausible that these limitations might result in increased BP.9 However, because some studies of patients with normal renal function have also been observed to have

Figure 1. In anemia, decreased blood viscosity leads to a phenomenon known as hypoxic vasodilation, which maximizes tissue oxygenation, and, consequently, decreases total peripheral resistance. As a compensatory response to decreased TPR, cardiac output increases. With correction of anemia, these events are reversed. If a rapid increase in hematocrit occurs in CKD, poor arterial and cardiac compliance as well as an inability to quickly decrease plasma volume to accommodate an increase in red cell volume is likely a mechanism that contributes to ESA-induced hypertension.

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Figure 2. Conceptual framework for a hypothetical association of ESA therapy and cardiovascular morbidity and mortality with de novo or exacerbated hypertension as an intermediate step. This illustrates that ESAs activate the erythropoietin receptor (EPO-R) on vascular endothelial cells and trigger a variety of intracellular signaling cascades, which lead to up-regulation and down-regulation of a variety of locally vasoactive substances as well as an increase in intracellular calcium. Collectively, the balance of these various vasodilator and vasoconstrictor factors may lead to a net increase in vascular tone, manifested as increased blood pressure.

an upward trend in blood pressure after treatment of anemia, there may be additional mechanisms, independent of the hemodynamic changes described, that mediate ESA-induced hypertension. These potential mechanisms are discussed below.12

POTENTIAL CAUSAL MECHANISMS FOR ESA-ASSOCIATED HYPERTENSION In addition to its presence on erythroid progenitor cells, the erythropoietin (EPO) receptor is expressed on vascular endothelial cells and smooth muscle cells, thus giving it a potential role in various cellular signal transduction pathways that culminate in vasoconstriction and possibly a BP increase (Fig. 2).14 Supporting a mechanism for an ESA-associated BP increase that is independent of, or perhaps additive to, the effect of blood volume and viscosity changes, Lee et al15 performed an experiment in a rat model to investigate differential systemic effects of the erythropoietin molecule. In this experiment, ESA was administered either alone or along with either a synthetic Epo-binding protein (Epo-bp) or Epo-bp plus an Epo-bp antibody. Rats that received an ESA alone experienced not only a significant increase in hematocrit but a significant increase in BP compared with placebo. The addition of the Epo-bp or Epo-bp plus Epo-bp antibody failed to attenuate the increase in hematocrit experienced with ESA alone but did attenuate the significant increase in BP. This suggests that separate epitopes on the erythropoietin protein exert differential physiologic effects, that is, there is a distinct epitope involved in mediating erythropoiesis and another that mediates the observed BP increase.

There are a variety of vasoactive substances whose expression and function have been shown to be altered by erythropoietin in both in vitro models as well as in vivo animal and human models that may contribute to an ESA-induced BP increase. Endothelin-1 Endothelin-1, a very potent vasoconstrictor, has been proposed as one mediator of ESA-induced hypertension. Takahashi et al16 conducted a study in 19 chronic HD patients treated with an ESA, 37% of whom experienced a significant increase in BP with a concomitant increase in immunoreactive endothelin concentrations. In subjects in whom BP did not increase significantly, endothelin concentrations did not increase. An in vitro model in which the aorta and carotid artery of rabbits were isolated under isometric conditions and treated with recombinant erythropoietin also showed an increase in endothelin-1, as did erythropoietin-treated human umbilical vein endothelial cells. However, other studies have failed to reproduce evidence of endothelin-1 up-regulation.17,18 The work by Yang et al18 not only failed to show endothelin upregulation but also raised the possibility of differential effects across various ESA agents. Yang et al18 investigated how erythropoietin-α versus darbepoetin affected tumor necrosis factor-α–induced endothelin-1 expression in cultured human aortic endothelial cells. They found that both of these agents actually decreased the expression of endothelin messenger RNA (mRNA), possibly by decreasing intracellular reactive oxygen species, which are thought to modulate signal transduction pathways that stimulate endothelin-1 expression. Darbepoetin was more potent in this regard than erythropoietin α. It was

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postulated that differences in the preparations of these two agents, namely the presence of more sialic acid–containing residues on the darbepoetin molecule (which is responsible for its longer half-life), might be responsible for the difference in potency. It must, of course, be kept in mind that in vitro studies such as those by Yang et al18 and others have failed to capture the complex in vivo relationships among biological and clinical factors. Renin-Angiotensin System Eggena et al19 used a rat model to evaluate mRNA expression of renin and angiotensinogen in plasma, kidney, heart, and aortic smooth muscle in the presence of recombinant erythropoietin. Rats exposed to recombinant erythropoietin alone and those concomitantly treated with an angiotensin-converting enzyme inhibitor had significantly higher measured BP than control animals not receiving the ESA. Kidney and aortic smooth muscle expressed both renin and angiotensinogen whereas heart and plasma did not. Another rat model showed heightened expression of renin, angiotensinogen, and the angiotensin receptor in vascular smooth muscle.20 As noted previously, in vivo human models have described a decrease in plasma renin and aldosterone levels as hematocrit increased with ESA use.12 This suggests that there might be differential effects of reninangiotensin-aldosterone expression at the tissue and plasma levels, and warrants further investigation. In a bench to beside study, Kuriyama et al investigated polymorphisms of the angiotensinogen gene in 51 patients with CKD (creatinine, 2.0-4.0 mg/dL) who had standardized BP monitoring before and after initiation of ESA therapy.21 Although reports were conflicting, data from meta-analyses have suggested that a missense mutation at codon 235 (the AGT T235 variant allele) is associated with an increased risk for essential hypertension.22,23 Among the 11 patients in Kuriyama's investigation who met the study criteria for ESA-induced hypertension (defined as an increase in mean arterial pressure by Z10 mm Hg during an 8-week observation period), homozygosity was expressed universally for the AGT T235 allele.21 Nitric Oxide Nitric oxide (NO) is a potent vasodilator that also has anti-aggregatory and antiproliferative actions. The importance of NO in modulating any hypertensive effect of ESAs or the resulting higher hemoglobin levels is highlighted by the findings generated from a study in transgenic mice that overexpressed human erythropoietin.24 Despite hematocrit levels as high as 80%, the mice did not develop hypertension but rather experienced a marked increase in endothelial NO synthase levels, circulating and tissue levels of NO,

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and NO-mediated endothelium-dependent relaxation. Administration of a NO synthase inhibitor led to vasoconstriction, marked hypertension, and death in these transgenic mice.24 A few studies have shown that the vasodilatory effect of NO is blunted in the setting of ESA-induced hypertension (HTN) either by reduced expression or by inhibited action. One mechanism by which this might occur is via alteration of upstream expression of enzymes that regulate NO production. For example, asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, is degraded by an enzyme called dimethylarginine dimethyl aminohydrolase. Erythropoietin has been shown to down-regulate dimethylarginine dimethyl aminohydrolase in a dosedependent manner, and thus lead to accumulation of ADMA, and, subsequently, inhibition of NO synthase. An increase of ADMA has been associated with endothelial dysfunction, oxidative stress, and atherosclerotic disease, all of which theoretically could contribute to the adverse events, including increased BP and thrombosis, which have been associated with ESAs.14,25,26 Alternatively, erythropoietin can attenuate the vasodilatory effect of NO. NO-induced vasodilation is triggered by a cyclic guanosine monophosphate (cGMP)-dependent mechanism, which decreases cytosolic calcium. Some studies have suggested that cytosolic calcium is increased by recombinant human erythropoietin, which independently increases vascular smooth muscle contraction and contributes to BP increase.27 For instance, Vaziri et al28 found in a rat model of chronic renal failure that erythropoietininduced hypertension was hematocrit-independent but was associated with an impaired vasodilatory response to NO and an increased concentration of intracellular calcium. In addition, the tendency to have higher cytosolic calcium levels with recombinant erythropoietin also might contribute to increased BP by attenuating the vasodilatory effect of NO by interfering with its cGMP-dependent mechanism.14 To investigate the relationship between cGMP and NO-induced vasodilation in the presence of erythropoietin, Ioka et al29 conducted an experiment in 56 HD patients treated with an ESA. Endothelial progenitor cells were isolated from these patients and mRNA levels for both the full erythropoietin receptor and a spliced, truncated receptor were measured. The investigators noted that, typically, activation of the erythropoietin receptor triggers a signaling cascade that ultimately terminates in cGMP and NO production and subsequent vasodilation. However, it was observed that in patients with exacerbated hypertension in the presence of the ESA, there was a positive correlation with the spliced, truncated variant of the receptor. This led to the conclusion that the truncated receptor variant of the receptor serves as a dominant negative regulator

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of the cGMP/NO cascade, thus blunting vasodilation, and potentially fostering an environment for BP increase. Prostaglandins Various prostaglandins have either vasoconstrictive or vasodilatory properties. An in vitro study on human endothelial cells by Carlini et al30 suggested that recombinant erythropoietin increases thromboxane A2 release, which is both a potent vasoconstrictor and stimulator of platelet aggregation. The same study also suggested a reduced release of prostacyclin, a vasodilatory prostaglandin, from human endothelial cells.25,30

META-ANALYSES Several meta-analyses, mostly heavily weighted by 4 large randomized trials (Table 1), have been conducted to examine important hard end points, such as cardiovascular morbidity and mortality, and to explore other clinical end points, such as BP (Table 2).31–34 Although none of these studies were designed with BP as a primary or secondary end point, there was no significant difference in the mean systolic BP in any of these 4 randomized controlled trials; the mean diastolic BP was higher in the higher hemoglobin group in 2 trials (Trial to Reduce Cardiovascular Events of Aranesp Therapy (TREAT) and Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta Trial (CREATE)), and was not different from the control group in 1 trial (Normal Hematocrit Trial). In one trial, the initial report indicated that diastolic BP increased less (P ¼ .02) in the high-hemoglobin group than in the low-hemoglobin group, but a secondary analysis reported a higher monthly average diastolic BP in subjects randomized to the higher hemoglobin arm and that increases in ESA dose and increases in hemoglobin level were associated with a higher diastolic BP.31,35 Cody et al36 included only trials of predialysis patients randomized to ESA therapy or placebo. The outcome of initiation of new antihypertensive medications or an increase in antihypertensive dose was analyzed from 4 trials (n ¼ 232 patients). The overall estimate effect was a relative risk ratio of 1.26, indicating a trend toward a greater risk of developing new or worsening hypertension in the ESA therapy group, but this was not statistically significant (95% confidence interval [CI], 0.76-2.11). Strippoli et al37 subsequently published a meta-analysis (n ¼ 1,664 patients; 8 trials) that separately analyzed studies that randomized patients to high versus low hemoglobin targets with ESA therapy (2 trials), and studies that randomized patients to ESA therapy versus placebo (6 trials). Outcomes evaluated included hypertension

S.M. Boyle and J.S. Berns

(defined by the addition of antihypertensive agents during the course of the trial or exclusion from the trial based on an adverse hypertension-related event), MAP, diastolic BP, and systolic BP. For the hypertension outcome, there were significantly fewer events in the placebo groups of studies randomized to placebo versus ESA therapy (relative risk (RR), 0.5; 95% CI, 0.33-0.76). The complementary analysis in the high versus low target trials trended toward fewer events in the low target group but was not significant (RR, 0.92; 95% CI, 0.59-1.45). All other outcomes were not statistically significant, with relatively large confidence intervals. Phrommintikul et al38 published another metaanalysis that included only larger studies (ie, at least 100 patients per RCT) with at least 12 weeks of followup evaluation (n ¼ 5,143; 9 trials), including both dialysis and predialysis patients. Because of the heterogeneity in BP documentation across the trials, only 4 of the 9 trials were included in their assessment of the outcome of poorly controlled hypertension.38 A fixedeffects model showed a statistically significant risk ratio of 1.27 (95% CI, 1.08-1.50), indicating higher risk for poorly controlled BP in the ESA/high-hemoglobin target group.38 However, when the analysis was performed with the more stringent random-effects model, the estimate of effect was no longer significant. After the TREAT study was published in 2009, an additional meta-analysis was conducted that included 27 trials (n ¼ 10,452 patients). The hypertension outcome included 12 trials (n ¼ 7,108) with both dialysis and predialysis patients. The relative risk of hypertension with ESA therapy with high target compared with ESA with low target was statistically significant at 1.67 (95% CI, 1.31-2.12).39 Finally, in a unique meta-regression analysis by Koulouridis et al,40 the exposure of ESA dose was evaluated on a variety of outcomes, including hypertension. This design allowed the investigators to examine whether outcomes were linked to ESA dose, independent of target hemoglobin. This analysis included 31 trials (n ¼ 12,956 patients). An unadjusted analysis showed a statistically significant incidence rate ratio for hypertension of 1.13 (95% CI, 1.03-1.24). However, when the analysis was adjusted for target hemoglobin, the magnitude of the incidence rate ratio decreased and was no longer statistically significant. Whether or not this was observed because a higher hemoglobin level is part of the causal pathway of ESA-induced hypertension is uncertain. When considered collectively, these meta-analyses suggest there is a trend toward higher BP with ESA use, either when compared with placebo or compared with ESA therapy with lower hemoglobin targets. However, as noted earlier, the RCTs that powered these meta-analyses were not designed to evaluate BP

Trial Name

Publication Year

Normal Hematocrit Trial

1998

CHOIR

2006

CREATE

2006

TREAT

2010

Design Randomized, multicenter, open-label study Randomized, multicenter, open-label study Randomized, multinational, multicenter, open-label study Randomized, multicenter, double-blinded study

Sample Size

Population Characteristics

Median Follow-Up Period, mo

1,233

Dialysis patients with ischemic heart disease or heart failure CKD with eGFR 15-50 mL/min

14

1,432

603

4,038

36

CKD with eGFR 15-35 mL/min

16

CKD with eGFR 20-60 mL/min; type 2 diabetes

29

Exposure(s)/Hgb Targets (g/dL)

Outcomes

Primary Hazard Ratio, Outcome, N 95% CI

Epoetin-α dose adjusted to Composite of all-cause High target, 1.3 (low target reference) 202; low mortality or nonfatal achieve a hematocrit of 30 (0.9–1.9) target, MI (Hgb, 9-11) versus 42 164 (Hgb, 13-15) High target, 1.34 (low Epoetin-α dose adjusted to Composite of death, 125; low target achieve Hgb of 13.5 hospitalization for target, 97 reference) versus 11.3 heart failure, (1.03–1.74) nonfatal MI, stroke High target, 0.78 (high Epoetin-β dose adjusted to Composite of 8 CV target events 58; low achieve Hgb of 13-15 reference) target, 47 versus 10.5-11.5 (0.53–1.14) Darbepoetin-α adjusted to achieve Hgb of 13 versus rescue darbepoetin to keep Hgb 4 9

Erythropoietin and resistant hypertension

Table 1. Large Randomized Controlled Trials of ESAs

Composite of all-cause High target. 1.05 (low target 632; low mortality and reference) target, cardiovascular (0.94–1.17) 602 events Composite of all-cause mortality or ESRD

Abbreviations: CHOIR, correction of anemia with epoetin alfa in chronic kidney disease; CV, cardiovascular; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; Hgb, hemoglobin.

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Table 2. Meta-Analyses of Randomized Controlled Trials of ESA With a Hypertension Outcome Study

Publication Year

Population

Cody et al

2005

Predialysis ESA versus placebo

Strippoli et al

2006

Predialysis, dialysis ESA versus placebo ESA/high target versus ESA low target

Phrommintikul et al Palmer, et al

2007

Predialysis, dialysis ESA/high target versus ESA low target Predialysis, dialysis ESA versus placebo ESA/high target versus ESA low target Predialysis, dialysis ESA versus placebo ESA/high target versus ESA low target

Koulouridis, et al

2010

2012

Outcome

Number of Studies

Number of Patients Relative Risk, 95 CI

Initiation of new antihypertensive medication 4 or intensification of current therapy HTN (defined by intensification of regimen or ESA versus placebo, 6 adverse event) ESA/high target versus ESA low target, 2

232

Poorly controlled HTN

4

1,744

HTN

12

7,108

De novo or worsening HTN

19

8,324

1,664

1.26 (0.76-2.11) Placebo* ESA versus placebo 0.5 (0.33-0.76) ESA* ESA/high target versus ESA low target 0.92 (0.59-1.45) ESA/high target* 1.27 (1.08-1.50) ESA/low target* 1.67, (1.31-2.12) ESA/low target* 1.13 (1.03-1.24) ESA/low target and placebo*

Abbreviation: HTN, hypertension. *Reference group.

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as an a priori outcome, and, thus, the quality in which BPs were measured and recorded across these studies is likely to be variable. It also should be noted that because the majority of the RCTs of ESA therapy were unblinded, open-label trials, the possibility of differential treatment of patients in the ESA arms, after randomization, also existed. If clinicians were aware of an ESA-BP association from the early literature, patients in the ESA arm of a study might have received closer attention and more aggressive antihypertensive therapy, with a tendency to make BP measurements more similar between the respective trial arms and to minimize or hide an ESA effect on BP.

AMBULATORY BLOOD PRESSURE MONITORING A few studies used ambulatory BP monitoring (ABPM) in the evaluation of the association between ESA therapy and BP increase. As a substudy of the Normal Hematocrit Trial conducted in hemodialysis patients, Berns et al41 studied patients randomized to high and low target hematocrit levels with ESA therapy while conducting ABPM over 12 months. Routine dialysis unit BP measurements as well as various ABPM assessments, such as mean 24-hour BP, mean daytime BP, and mean nighttime BP were not statistically significantly different between the two groups. In the predialysis population, a very small prospective observational study of 11 patients with an average baseline creatinine clearance of 13 mL/min who were receiving ESA therapy found no significant difference in either daytime or nighttime systolic or diastolic blood pressure between any of the ABPM periods.42 Although small sample size was a limiting factor with both of these studies, they were consistent in that neither found a statistically significant increase of BP with ESA therapy.

THE TREAT STUDY AND ESA STROKE RISK As we consider the potential association between ESA therapy and hypertension among larger clinical trials, the relatively recently TREAT study warrants special attention. TREAT was the largest RCT of ESA therapy (n ¼ 4,038). It was also one of the few RCTs to be double-blinded, randomizing patients to either a hemoglobin target of 13.0 g/dL with darbepoetin or placebo with ESA “rescue” to keep hemoglobin from drifting below 9.0 g/dL.34 This study showed a statistically significant increased hazard of stroke in patients randomized to the ESA/high-hemoglobin target arm. A post hoc analysis of this study did not detect a significant association between stroke risk and BP, either at baseline or after randomization, including the latest BP value before a stroke. Among darbepoetintreated subjects, the last measured mean systolic and

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diastolic BP in the 90 days before a stroke was virtually identical in those with a stroke (135/72 mm Hg) and in those who did not suffer a stroke (134/72 mm Hg) in the same time period, and in placebotreated subjects with (136/70 mm Hg) and without a stroke (137/72 mm Hg).43

CONCLUSIONS Current data support an association between ESA therapy (either alone or in conjunction with a concomitant increase in hematocrit) and hypertension. It is not yet possible to designate a specific causal role for ESA therapy in de novo or exacerbated hypertension in CKD patients. It is also premature to assign ESAinduced hypertension an intermediary role linking ESA therapy with increased cardiovascular morbidity and mortality rates documented in recent RCTs. Despite this, the available data on ESA-induced hypertension in CKD suggests that it is essential to carefully monitor BP in both predialysis and dialysis patients treated with an ESA. The Kidney Disease Improving Global Outcomes 2012 guidelines provided very reasonable recommendations for managing ESA therapy.6 In addition, we suggest that when initiating ESA therapy in patients with a history of resistant hypertension, seizure, or hypertension-related hemorrhagic stroke, clinicians should choose doses at the lower end of the recommended range. Furthermore, it is very important to closely monitor the rate of hemoglobin increase. In patients with a high BP at the start of treatment or who have variable BP control, home BP monitoring may allow early detection of a BP increase with initiation of ESA therapy or after an escalation in dose. Hemoglobin levels should not increase at a rate greater than 1 g/dL in a 2-week period. A faster hemoglobin increase should prompt a dose reduction of at least 25%. As stated in the Kidney Disease Improving Global Outcomes 2012 guidelines, the goal of ESA therapy should not be to target complete correction of anemia, but rather to alleviate symptoms and avoid transfusion to prevent alloimmunization, with a hemoglobin target that generally should not exceed 11.5 g/dL.6 There are, of course, many factors that influence BP, including medication compliance and volume status. ESA-induced or exacerbated hypertension is a diagnosis of exclusion. We suggest optimizing BP via antihypertensive medications and volume status, through either diuretic therapy or, in the case of dialysis patients, with ultrafiltration, before adjusting the ESA dose. For dialysis patients, it may be prudent to achieve a reasonable dry weight before starting an ESA. In the absence of specific data to inform decisions regarding whether to give or withhold an ESA dose in a patient with increased BP, it is our usual

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practice to postpone ESA administration in patients with a BP higher than 160/90 mm Hg. Given that some basic science and translational studies suggest that ESA mediates an increase in BP via mechanisms such as increasing cytoplasmic calcium concentrations in smooth muscle cells or increasing angiotensin levels in the vascular endothelium, one might speculate that agents such as calcium channel blockers, angiotensin-receptor blockers, and angiotensinconverting enzyme inhibitors could be useful in the management of ESA-induced hypertension.25 By the same token, the relatively rapid increase in hematocrit that accompanies ESA therapy might require downward regulation of plasma volume, thus suggesting a more prominent role for diuretic therapy or ultrafiltration to optimize volume status.

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